Oxaliplatin inhibits proliferation and migration of human hepatocellular carcinoma cells via GAS7C and the N-WASP/FAK/F-actin pathway
Oxaliplatin inhibits proliferation and migration of human hepatocellular carcinoma cells via GAS7C and the N-WASP/FAK/F-actin pathway
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DOI：
10.1093/abbs/gmx046
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发表时间：
2017-07-01
影响因子：
3.7
通讯作者：
Hu, Chao
中科院分区：
文献类型：
--
作者：
Li, Dan;Zhang, Bin;Hu, Chao
生长停滞特异性基因7（growth arrest-specific gene 7，GAS 7）是生长停滞特异性基因家族的成员之一，编码3种蛋白质亚型（GAS 7A、GAS 7 B和GAS 7 C），是一种潜在的肿瘤抑制基因。在本研究中，我们发现与正常肝细胞相比，肝细胞癌（HCC）细胞系中GAS 7 C mRNA和蛋白的内源性表达较低，并且在奥沙利铂处理的HCC细胞中GAS 7 C表达明显增加。CCK-8、细胞凋亡和Transwell迁移实验表明，奥沙利铂可抑制HepG 2和MHCC-97 H细胞的增殖和运动，而增加细胞凋亡。有趣的是，蛋白质印迹分析显示，在两种HCC细胞系中，奥沙利铂处理增加了GAS 7 C和N-WASP蛋白水平，并降低了参与纤连蛋白/整联蛋白/FAK途径的蛋白质水平，如FAK。此外，异位过表达的GAS 7 C明显抑制细胞增殖和细胞运动。流式细胞仪检测结果显示GAS 7 C过表达可诱导HepG 2和MHCC-97 H细胞凋亡。我们进一步通过q-PCR和蛋白质印迹分析GAS 7 C过表达的HepG 2和MHCC-97 H细胞中GAS 7 C和N-WASP/FAK/F-actin途径之间的相关性。抑制GAS 7 C可显著逆转奥沙利铂的抗癌作用，并阻断N-WASP/FAK/F-actin途径的活性。综上所述，我们的结果表明，奥沙利铂通过上调GAS 7 C和激活N-WASP/FAK/F-actin途径抑制HCC细胞增殖和迁移能力。
The growth arrest-specific gene 7 (GAS7), a member of the growth-arrest-specific family, encodes three protein isoforms (GAS7A, GAS7B, and GAS7C) and plays a potential role in lung cancer as a tumor suppressor gene. In the present study, we found low endogenous expressions of GAS7C mRNA and protein in hepatocellular carcinoma (HCC) cell lines compared with normal liver cells, and that there was a distinct increase of GAS7C expression in HCC cells treated with oxaliplatin. CCK8, apoptosis, and Transwell migration assays showed that cell proliferation and motility of HepG2 and MHCC-97 H cells were inhibited by oxaliplatin, while apoptosis was increased. Interestingly, western blot analysis showed that treatment with oxaliplatin increased GAS7C and N-WASP protein levels and decreased the levels of proteins involved in the fibronectin/integrin/FAK pathway, such as FAK, in both HCC cell lines. In addition, ectopically overexpressed GAS7C obviously inhibited cell proliferation and cell motility. Flow cytometry results showed that overexpression of GAS7C induced apoptosis of HepG2 and MHCC-97 H cells. We further confirmed the correlation between GAS7C and the N-WASP/FAK/F-actin pathway by q-PCR and western blot analysis of in GAS7C-overexpressing HepG2 and MHCC-97 H cells. Inhibition of GAS7C substantially reversed the anti-cancer effect of oxaliplatin and blocked the activity of the N-WASP/FAK/F-actin pathway. Taken together, our results showed that oxaliplatin inhibits HCC cell proliferation and migration ability by up-regulating GAS7C and activating the N-WASP/FAK/F-actin pathway.